Synthesis and charecterisetion of potential anti-cancer bisnitrogen mustards, and determination of their DNA binging activity

Nitrogen mustards are the oldest synthetic alkylating agents that was reported to use in cancer treatment in 1940s that are still being used. They were synthesised by the modification of sulfur mustard which was used as a gas-weapon during World War I. They are bifunctional alkylating agents that alkylate to DNA on guanine site (N-7) and make cross-link between intrastrand and inter-strand. They have great role for the treatment of hodgkin's disease multiple myeloma, colon cancer, prostate cancer and breast cancer. Nitrogen mustards as Mechloretamine, Chlorambucil, Melphalan are very reactive compunds. Notwithstanding, they are usually use with another codrug on chemothrapy. This situation catches scientist's interest who search new agent. They are studying to increase effective of nitrogen mustards on cancer cells. Besides that most of scientist too are researching for mechanism of action of current agents. Knowledge of mode of action between target and agent is important to discovery of more effective agent. In this thesis, a number of studies were conducted in order to increase effectiveness and to elucidating the mechanism of action of novel clinically nitrogen mustards. For this purpose, the HDL (with tetra-alkylation capacity) molecule containing two-headed nitrogen mustard (Chlorambucil) unlike normal nitrogen mustards were designed and synthesised. Then activity and the mechanism of action of HDL were investigated. Plasmid DNA cleavage studies, chemical activity with NBP (4-(p-nitrobenzyl)pyridine) and mono-alkylation and/or cross-link on synthetic oligonucleotide was investigated. As a result of these experiments, it was observed the HDL molecule was found to have plasmid DNA cleavage activity, and also were found to be much more reactive than chlorambucil in their chemical activity studies and cross-linked in cross-linking studies. In the mono-alkylation studies performed with the Maxam-Gilbert method. The guanine was found to be alkylated with the HDL molecule. The obtained data indicate that bis-nitrogen mustard (HDL) is chemically more reactive than mono-nitrogen mustard. Therefore, it has been found to have potency to be used as a chemotherapeutic agent